Injuries to the bone marrow and gastrointestinal (GI) tract are the prinnary determinants of survival after exposure to ionizing radiation. Progress has been made in the management of hematopoietic radiation injury. In contrast, the management of GI radiation toxicity remains underdeveloped, and countermeasures specifically against intestinal radiation injury are urgently needed. We discovered that a novel somatostatin analog, SOM230, substantially reduces lethality, prolongs survival, and reduces both structural bowel injury and bacterial translocation in mice after total body irradiation (TBI). We also showed that the mechanism involves inhibition of exocrine pancreatic secretion into the gut lumen. Most remarkably, SOM230 retains its lethality-protecting properties even when administration begins 48+ hours after TBI, a realistic time-frame in a mass casualty situation. Thus, SOM230 is an effective radiation mitigator that ameliorates/restores gut structure and function long after the initial damage has occurred. This project will advance SOM230 toward approval by the Food and Drug Administration (FDA) by addressing mechanistic aspects related to its properties as a radiation mitigator and attempting to further enhance logistics and/or efficacy. We proposed to determine 1) the relative significance of GI versus hematopoietic injury; 2) the specific requirement for somatostatin type 2 receptor; 3) if the number of injections can be reduced by the combination with a longacting somatostatin analog; and 4) whether the mitigating properties can be further enhanced by the combination with gamma-tocotrienol (GT3), a unique vitamin E analog that is currently in advanced development as a radioprophylactic agent. This work has a strong basis in preliminary data and utilizes well established radiation models and physiological assays combined with contemporary molecular techniques. It is highly collaborative with other projects in this program and utilizes several of its cores. These studies will move SOM230 fonward on the drug development path toward FDA approval as a medical countermeasure against radiological emergencies and will have a significant and immediate impact on human health.